Intermediates in synthesis of pregnadiene

ABSTRACT

The invention comprises compounds having the following formulae &lt;FORM:0984024/C2/1&gt; wherein R is a hydrogen atom or an alkanoyl group having not more than 8 carbon atoms. These compounds are obtained by subjecting a 17-oxo compound having the formula &lt;FORM:0984024/C2/2&gt; to a Grignard reaction to obtain the 17a -methyl - 17b  - hydroxy compound which on dehydration yields the D 16-17-methyl compound. Dehydration may be effected with phosphorus oxychloride. Specification 873,019 also is referred to.

United States Patent 3,197,485 INTERMEDIATES 1N SYNTWSIS 0F PREGNADIENE Wataru Nagata, Hyogo Prefecture, Japan, assignor to Shionogi & Co., Ltd., Osaka, Japan No Drawing. Filed July 18, 1962, Ser. No. 210,842 Claims priority, application Japan, Mar. 12, 1960, 35/

8,208; Mar. 19, 1960, 35/9,421; Apr. 4, 1960, 35/

20,124, BIS/20,125; Apr. 6, 1960, 35/20,723; Apr. 21,

1960, 35/22,417; Apr. 25, 1960, 3S/22,611; July 19,

18 Claims. (CI. 260-3409) This application is a continuation-in-part of copending application Serial No. 127,097, filed July 27, 1961.

This invention relates to the synthesis of the pregnadiene represented by the following formula:

to glfi HO W (I) wherein the ripple mark (3) is a generic indication of both the w and fi-configurations, and to intermediates useful in such synthesis.

The pregnadiene I is useful as an intermediate in the synthesis of pharmacologically active steroids such as cortisone, hydrocortisone, prednisolone and dexamethasone.

Accordingly, a primary object of this invention is to provide a useful compound for the synthesis of pharmacologically active steroids and intermediates thereof. Another object of this invention is to provide a synthetic method for the preparation of pharmacologically active steroids. A further object of the invention is to provide a novel total synthetic method for the production of steroids of pregnane series. Other objects Will be apparent to those skilled in the art to which this invention pertains.

The position-numbering employed herein for the ste roidal type compounds is that generally accepted in steroid chemistry, i.e.,

ANA

unless some other numbering is specially mentioned.

The method of this invention is generically outlined in the following reaction scheme:

3,197,485 Patented July 27, 1965 Ste II Step III HO ON l -O I Step IV HO NW Step V HO Nw H (VI) OH I .011

Step VI HO w Step VII HO Nw (VIII) CH W CH0 I V StepVIH HONW scheme. In other words,'the showing of an hydroxyl radical is intended to represent a free hydroxyl or a protected hydroxyl such as acylated hydroxyl, preferably a lower alkanoyloxy (e.g., acetyloxy, propanoyloxy, butanoyloxy), a benzoyloxy or a lower alkylbenzoyloxy (e.g., tolylcarbonyloxy, xylylcarbonyloxy), and the showing of an oxo radical is intended to represent a free oxo or a protected OX such as ketalized oxo, preferably a lower alkylenedioxy (e.g., 'ethylenedioxy, propylenedioxy).

The starting material of the present invention is 3-hydroXy-D-homo-18-nor-androst-1 3 17a) -en-17-one. of Formula II, i.e., 3u-hydroXy-D-homo-18-nor-5u-androst- 13(17a)-en-17-one of Formula IIa, 3u-hydroXy D-homo- 18-nor-5B-androst-13(17a)-en-17-one of Formula 11b, 35 hydroxy D-horno-18-nor-5u-androst-13(17a)-en-17- one of Formula I10 and 3fl-hydroxy-D-homo-l8-nor-5B- androst-13(17a)-en-l7-one of Formula IId. The A enone II, which is described and claimed in my copending application, Serial No. 127,097, filed July 27, 1961,

can be prepared by refluxing mildly 6-methoXy-2-tetralone of Formula A with an equimolar amount of -di-.

ethylaminoethyl ethyl ketone in anhydrous ether in the presence of sodium hydride, reacting the resultant mixture containing a tautomer of 1-methyl-7-methoxy-1,2,3, 3,9,10-hexahydrophenanthreh-Z-one of Formula B with an equimolar amount of B-diethylaminoethyl methyl ketone at about 0 to 5 C. followed by refiuxing, and subjecting the thus-obtained 2-methoxy-10a-methyl-5,6,8,9, 10,10a,11,12-octahydrochrysen-8-one of Formula C to reduction in a variety of per se conventional manners. These steps are representable 'by the following scheme:

radical and/ or the oxo radical in a per se conventional manner. However, whether the protection is necessary or not may be obviousto those skilled in the art. The hydroxyl radical is usually protected by acylation, which can be carried out by treating the hydroxyl compound 15 with an acylating agent in the presence of a condensing agent. For instance, the hydroxyl compound may be converted into the corresponding acetoxy compound by treating with acetic anhydride in the presence of pyridine or p-toluenesulfonic acid. Subsequent deacylation, if desired, can be easily carried out by treatment of the aeyloxy compound with alkali, usually while heating. The pro cedure generally employedfor protecting an 0x0 radical is ketalation, which can 'be realized by treatment of an oxo compound with an alcohol in the presence of a condensing agent. For instance, the ketalation may be carried out by heating the 0x0 compound with ethanol or ethyleneglycol in the presence ofp-toluenesulfonic acid in an organic solvent medium such as benzene or toluene. Subsequent deketalation, if desired, can be easily carried out 'by heating the ketaolized compound with acid. Some of these reactions, i.e'., acylation, deacylation, ketalation and deketalatiou, may proceed simultaneously with the main reaction in some steps.

0 3 OCHz o 0 Hi I on,- V

Aalytie reduction with Hg in the presence of Pd (1) Reduction with Li in liq. N 3 ethanol (2) Reflux with H01 in methanol (1) Reduction with Li in liq N H? ethanol (2) Reflux with H01 in methanol i The separation of the pregnadiene II (Ila, III), 110 or '-IId) from its isomeric mixture can be readily accomraphy) V A HO EO (IId) (IIb) HO--- (11c) H V H Firstly, the starting A -enone II is subjected to double bond formation comprising enolation, halogenation and dehalogenation to give the A -dien0ne III. The enolaplished by a conventional procedure (e.g., chromatog- 7 r tion may be attained by a conventional enolesterification or enoletherification procedure. For instance, the enolesterification can be accomplished by refluxing the A enone II with a mixture of isopropenyl acylate (e.g., iso propenyl acetate, isopropenyl proprionate) and an acid (e.g., sulfuric acid, p-toluenesulfonic acid) and the enoletherification accomplished by refluxing the A -enone II with alkyl orthoformate (e.g., methyl orthoformate, ethyl orthoformate) in the presence of a basic substance (e.g., pyridine, picoline, triethylamine) in an inert solvent (e.g., methanol, ethanol, benzene, toluene). The subsequent halogenation and dehalogenation can be performed by treating the resulting enolated compound with a halogenating agent, preferably a brominating agent (e.g., bromine, N-bromosucciuic imide) in an inert solvent (e.g., acetic acid, collidine) followed by treatment of the resulting halogenated substance with lithiumv bromide and lithium carbonate in an inert solvent (e.g., dimethylformamide, ether) while refluxing.

Secondly, the A -dienone III is subjected to movement of double bond comprising enolation and hydrolysis to give A -dien0ne IV. Although the enolation may be carried out in the same manner as in Step I, the enoletherification is preferably adopted, because the elimination of the enolether group in the following hydrolysis can be accomplished under a relatively mild condition. The hydrolysis is preferred to be carried out under a mild condition, i.e., by treating the enolated compound with a weak acid (e.g., acetic acid) at about 70 to 100 C.

Thirdly, the A -dienone IV is subjected to angular cyanation to give the nitrile V. The cyanation may be carried out according to a novel angular cyanation procedure, which is described and claimed in my copending application, Serial No. 127,097, filed July 27, 1961. Thus, the reaction can be performed by treating the A -dienone IV with a cyanating agent (e.g., alkali metal cyanide, alkaline earth metal cyanide, lithium aluminum cyanide, cyanomagnesium halide alkylaluminum cyanide, cyanoalkylaluminum halide), preferably in the presence of a catalyst (e.g., ammonium halide, acetic acid, ammonium acetate, alkali bisulfite), in an inert organic solvent (e.g., lower alkanol, ether, hydrocarbon, dialkylformamide, dioxane, tetrahydrofuran) at about to 100 C. More preferably, Lewis acids or suitably bases (e.g., trialkylamine, aluminum trialkoxide, alkylaluminum alkoxide,

trialkylaluminum, alkylaluminum halide) may be used in combination with hydrocyanic acid in an inert organic solvent as described above except lower alkanol.

Foutthly, the angular cyano group of the nitrile V is converted into the methyl group. The conversion comprises reduction, hydrolysis and reduction. The first reduction can be accomplished by treating the nitrile V with a metal hydride (e.g., lithium aluminum hydride, sodium aluminum hydride, magnesium aluminum hydride, aluminum hydride, lithium aluminum alkoxyhydride) in an inert organic solvent (e.g., tetrahydrofuran, ether) at a temperature not lower than room temperature. The following hydrolysis may be carried out by treating the resulting reduction product with alkali (e.g., sodium hydroxide, potassium hydroxide) while refluxing. The second reduction may be accomplished by converting the above-prepared hydrolyzing product into the semicarbazone, hydrazone, or azine in a per se conventional manner and heating the latter with a basic catalyst (e.g., sodium, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide) in the presence or absence of an inert organic solvent (e.g., methanol, ethanol, diethyleneglycol, triethyleneglycol) Fifthly, the thus-prepared a -enone VI is subjected to methylation at l7-position to give the A -enol VII. The methylation may be carried out by treating the A -enone V1 with methyl magnesium halide (e.g., methyl magne-' sium iodide, methyl magnesium bromide) in an inert organic solvent (e.g., tetrahydrofuran, benzene, toluene, ether), followed by hydrolysis.

Sixthly, the A -enol VII is subjected to dehydration to 6 give the ag' -diene VIII. The dehydration can beexecuted by treating the A -enol VII with a dehydrating agent (e.g., phosphorus oxychloride, phosphorus oxybromide, phosphorus pentoxide). For instance, the A -eno1 VII is treated with phosphorus oxychloride in pyridine at 50 to C. to yield the A -diene VIII. The product in this step is a mixture of the A -dime VIII and its isomer having the following formula:

wherein the ripple mark (2) is a generic indication of both the aand B-con-figurations. Hereupon, the mixture may :be subjected to the reaction in the following step as it is, because the separation of the by-product can be readily accomplished in that step.

Seventhly, the A -diene VIII is subjected to oxidative ring-fission to give the 16-aldehyde IX. The ring-fission may be performed by treating the A -diene VIII with a variety of oxidizing agents (e.g., oxygen-ozone, potassium permanganate, osmium tetroxide, periodic acid, perbenzoic acid, hydrogen peroxide). For instance, the A -diene VIII is treated with osmium tetroxide in an inert solvent (e.g., benzene, toluene, ether, dioxane) at room temperature, followed by treatment with hydrogen sulfide, and the resulting oxidation product is treated with periodic acid in an inert solvent (e.g., methanol, ethanol, dioxane, tetrahydrofuran) at room temperature to give the l6-aldehyde IX. As stated above, the A -dime VIII may be generally subjected to the reaction in this step as an isomeric mixture with the A -diene VIII. In such case, the reaction product is a mixture of the 16- aldehyde IX and its isomer having the following formula:

(VIII') CHO wherein the ripple mark (i) is a generic indication of both the aand fi-configurations. Although the mixture may be employed in the following step without separa tion, it is preferred to separate each component after or in the course of this step. The separation can be readily accomplished by a conventional procedure (e.g., chromatography).

Lastly, the lfi-aldehyde IX is subjected to cyclization to give the objective pregnadiene I. The cyclization may be accomplished by heating the. lfi-aldehyde IX with a basic substance (e.g., diethylamine, triethylamine, tripropylami-ne, piperidine) in an inert solvent (e.g., benzene, toluene, xylene).

Although the method of this invention is hereinbefore illustrated step by step, some of these steps may be executed successively Without the isolation of the product in each step.

The final product is the pregnadiene I, i.e., 3cx-hYdIOXY- 5a-pregna-9(11),l6-dien-20-one of formula Ia, Eta-hydroxy-5,8-pregna-9(11),16-dien-20rone of formula lb, 3 3- CH3 0H3 hydr0xy-5u-pregna-9-(11),16-dien-20-one of formula 10 I (E0 and 35-hydroXy-5/3-pregna-9(1=1),16-dien-20-one of .for- 'o I O v I mula Id. i I 1 CH3 CH3 V r V HO- 7 V I HO- W 10 15 w) For illustration, a typical conversion of 3a-hydroxy- D-homo-l8-nor-5fi-androst-13(17a)-en-17-one 11b into Ho", o tho corresponding final product, 3a hydroxy-5fi-pregna- H (Ia) H (I17) 15 D-homo-18-nor-5 B-androst-l3(17a) en 17-one IIb into invention is set forth in the following scheme:

5 mo R50 m0--- wherein R, R, R", R and R each represents a lower allranoyl group (e.g., acetyl, propanoyl, butanoyl), R represents a lower alkyl group (e.g., methyl, propyl, butyl, ethyl) and A represents a lower alkylene group (=e.g., ethylene, trirnethylene).

The said final products are equally useful as intermediates in the synthesis of pharmacologically active steroids of pregnane series such as cortisone, hydrocortisone, prednisolone and dexamethasone. For instance, the pregnadiene 1c is converted into cortisone according to a conventional method [Callow et al.: J. Chem. Soc., '9. 4739 (1956); Rosenkranz et al.: I. Am. Chem. Soc., 73, p. 4055 (1951); Rosenl anz et al.: Nature, 168, p. 28 (1951)]. The other products also can be converted into cortisone in the substantially same manner as illustrated above, if necessary, with some changes being obvious to those skilled in the art. For instance, the pregnadiene 112 is converted into 3a,17m-dihydroXy-5,8-pregna-11,20-dione in the same manner as illustrated above [Callow et al.: J. Chem. Soc., p. 4739 (1956)] and then the latter may be converted to cortisone according to a conventional manner [K-ritchevsky et al.: J. Am. Chem. 800., 74, p. 483 (1952)].

The following examples illustrate presently-preferred methods of carrying out the present invention.

Example 1 OCH;

coon,

( soon over 0.6 g. of 10%-palladium-carbon at 25 C. under an atmospheric pressure. For minutes, 329 ml. of hydrogen is absorbed. (Theoretical absorbtion under an atmospheric pressure at 25 C.: 247 ml.) Then, the catalyst is removed by filtration and washed with ethanol. The filtrate and the washing solution are combined and evaporated under reduced pressure to give 3.2 g. of residue. The residue is crystallized by treatment with cold ethanol or cold methanol to give 2.49 g. of dl-17-methoxy- D-homo-lS-nor-Sfi-androsta-S,13,15,17-tetraen 3 one as scales. Recrystallization from cold ethanol gives pure product melting at 82-85 C. U.V. (EtOH): 273 mu (616,000). LR. {CHC13): 1714, 1612, 1576, 1503 cm.

Analysis.Calcd. for C H O (296.39): C, 81.04; H, 8.16. Found: C, 80.73; H, 8.24.

Example 2 'OCH3 OCHa To a solution of 2 g. of tri-t-butoxyaluminium lithium hydride in 10 ml. of anhydrous tetrahydrofu-ran is added another solution of 1 g. of dl-17-methoxy-D-homo-18- nor-SB-androsta-S,13,15,17-tetraen-3-one in 10 ml. of anyhydrous tetrahydrofuran under ice-cooling, wherein the addition takes 15 minutes. The reaction'mixture is stirred for 10 minutes under ice-cooling and for 2 hours at room temperature. Then, 2 ml. of water and 10 ml. of 2 N-hydrochloric acid are added under ice-cooling to decompose the excess of tri-t-butoxyaluminum lithium hydride and the mixture is extracted with ether. The ex- Example 3 -oona H l 4%. H

To a solution of 9 g. of metallic lithium in 270 m1. of liquid ammonia (freshly distilled in the presence of metallic lithium) is dropwise added another solution of 3 g. of dl-17-methoxy-D-homo-18-nor-5li-androsta 8,13,15, 17-tetraen-3a-ol in a mixture of 22 m1. of anhydrous dioxane, 46 ml. of anhydrous ether and .38 ml. of anhydrous ethanol, wherein the dropwise addition takes 1.5 hours. After 15 minutes the excess of metallic lithium is inactivated by addition of 50 ml. of anhydrous ethanol and then liquid ammonia is evaporated. To the residue is added water under ice-cooling and the mixture is extracted with ether. The extract is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 3.0 g. of residue. To a boiling solution of the residue in a mixture of 125 ml. of methanol is added 50 ml. of 4 N-hydrochloric acid Within minutes and then the mixture is refluxed for 10 minutes. The reaction mixture is chilled, poured into ice-Water and extracted with chloroform. The extract is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 3.0 g. of oily residue. Crystallization from ether gives 906.4 mg. of crystals melting at 168-171 C. The mother liquor is chrom-otographed on 60 g. of'neutral alumina. From eluates with benzene-chloroform (8:2-2) mixture is obtained 179.5 mg. of crystals melting at 169- 171 C. Totally, 1.086 g. of dl-3a-hydroxy-D-homo-18- nor-5fl-androst-l3(17a)-en 17-one is obtained. On the other hand, from eluates with benzene and benzenechloroform (8:2) mixture is obtained 305.3 mg. of another product melting at 164165 C. This product is a steric isomer as to the B/ C juncture, but its strict configuration has never been determined.

Recrystallization of dl-3a-hydroxy-D-homo-18-nor-5fi- .androst-13(17a)-en-17-one from acetone-ether mixture gives pure product melting at 17017l C. as plates.

U.V. (tOH): 241.3 mg (e16,820).

1662, 1645, 1617 cmr Analysis-Calcd. for C I-1 0 08841): C, 79:12; H,

9.79. Found: C, 78.96; H. 9.60.

' Recrystallization of the isomer from acetone-ether mixture gives pure compound melting at 168-169 C. as

1 plates. This M.P. is apparently depressed on admixture with dl-3a-hydroxy-D-homo-1S-nor-Sfl-androst- 13 17a) LR. (Nujol): 3460, I

1'2 Example 4 HO" CH COO--- To a solut-ion of 400 mg. of dl-3a-hydroxy-D-homo-18- nor-5fl-androst-13(17a) en-17-one in 5 ml. of isoprope-nyl acetate is added 20 mg. of p-toluenesulfonic acid monohyd-rate and the mixture is refluxed for 4 hours at C. under nitrogen current. After addition of sodium acetate, the mixture is concentrated under reduced pressure and then extracted with ether. The extract is Washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 511.3 mg. of oily residue. The residue is crystallized from etherpentane mixture to give 195.7 mg. of dl-3oc,17-di3.06tOX D-homo-18-nor-5B-androsta-12,17 diene. Recrystallization from ether-pentane mixture gives pure crystals melting at 97-109 C. U.V. (EtOH): 235 m (e18,840).

Analysis--Calcd. for C H O (372.49): C, 74.16; H, 8.66. Found: C, 74.33; H, 8.69.

Example 5 To a solution of 6.8 g. of dl-3a-hydroxy-D-homo-18- nor-5,8-androst-13(17a)-en-17-one in 90 ml. of isop-ropenyl acetate is added 330 mg. of p-toluensulfonic acid monohydrate and the mixture refluxed for 4 hours on an oil bath C.) with'stirring under nitrogen current. After addition of 350 mg. of sodium acetate, the mixture is concentrated under reduced pressure and extracted with ether. The extract is Washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 9.6 g. of oil residue.

' To a solution of this oily residue in 137 ml. of acetic acid is added 51 ml. of collidine under ice-cooling. Then 42 ml. of 10%-bromine-acetic acid solution is added dropwise with good stirring under ice-cooling, the dropwise addition taking 30 minutes. The mixture is then stirred at 1520 C. for 20 minutes and poured into 1000 ml. of cold water containing 256 g. of sodium bicarbonate and extracted with ether. The extract is washed with water, and dried over anhydrous sodium sulfate.

To a dimethylformamide solution containing'10.5 g. of lithium bromide and suspending 10.5 g. or" lithium carbonate is added the ether solution prepared above with stirring. After distilling 01f ether, the mixture is refluxed for 40 minutes under nitrogen current, then cooled reaction mixture is :poured into a mixture of 51 ml. of acetic acid and 510 ml. of water and extracted with ether. 7

The extract is Washed with 2 N-sodium carbonate and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 9.1 g. of oily residue. The residue is dissolved in 25 ml. of pyridine and 15 ml. of acetic anhydride and allowed to stand over night. Thus obtained crude oily acetylate (8.76 g.) is chromatographed on 250 g. of neutral alumina. From eluates with petroleum ether-benzene (2:1) mixture, petroleum ether-benzene (1:1) mixture, petroleum ether-benzene (1:2) mixture and benzene is obtained 2.42 g. of crystals melting at 148-152" C. by recrystallization from etherpentane mixture.

Combined oily residue (1.43 g.) from mother liquors and uncrystallized fractions is chromatographed on 30 g. of neutral alumina. From eluates with petroleum etherbenzene (2:1) mixture and petroleum ether-benzene (1:1) mixture is obtained further 172.2 mg. of crystals melting at 147149 C. by recrystallization from etherpentane mixture. Totally, 2.6 g. of dl-3a-acetyloxy-D- homo-1S-nor-SB-androsta-ILB(17a)-dien-17-one is obtained. Further recrystallization from ether gives pure product melting 149-15 1 C. as needles. U.V. (EtOH): 285 mu (6 28,840). LR. (Nujol): 1724, 1660, 1617, 1585, 1243, 1254 CHIC-1.

Analysis.Calcd. for C H O (328.44): C, 76.79; H, 8.59. Found: C, 76.67; H, 8.59.

Example 6 AFC CH COO-- A mixture of 290 mg. of dl-3a-acetyloxy-D-homo-lfinor-fi-androsta-1L13(17a)-dien-17-one, 30 mg. of pyridine hydrochloride, 1.8 ml. of ethyl orthoformate, 1.5 ml. of anhydrous ethanol and 15 ml. of anhydrous benzene is refluxed for 3 hours on an oil bath and then poured into a mixture of 28 ml. of 2 N-sodium carbonate solution and ml. of ether under ice-cooling. The ether layer is separated and the aqueous layer is extracted twice with ether. All of ether layers are combined, washed with water, dried over anhydrous sodium sulfate and evaporated. The residue is treated with ethanol to give 170.8 g. of crystals. The mother liquor is evaporated and the residue (171 mg.) is chromatographed on 2 g. of alumina. From eluates with petroleum ether-benzene (9:1) mixture, petroleum ether-benzene (8:2) mixture, petroleum ether-benzene (7:3) mixture and petroleum ether-benzene (5:5) mixture is obtained further 10.5 ml. of crystals by recrystallization from ether-pentaue mixture. Totally, 181.3 mg. of dl-3a-acetyloxy-l7-ethoxy-D- homo-l8-nor-5fl-androsta-9( 1 1 ,12,17-triene is obtained. Recrystallization from ether-pentane mixture gives pure product melting at 118-122 C./ 130 C. as fine columns. U.V. (EtOI-l): 321 m (6 20,870). LR. (Nujol): 1723, 1641, 1621 cm.-

Analysis.Calcd. for C H O (356.49): C, 77.49; H, 9.05. Found: C, 77.39; H, 9.09.

Example 7 -0o2rr omcoo--- orntloo- 0N p -0 I To a solution of 232 mg. of dl-3u-acetyloxy-17-eth0xy- D-homo-18-nor-5B-androsta-9(11),12,17-triene in 8 m1. of glacial acetic acid is added 8 ml. of water and heated for 15 minutes at C. on a Water bath. Then, at once, the reaction mixture is concentrated under reduced pressure and the concentrate is extracted with ether. The extract is Washed with 2 N-sodium carbonate solution and Water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 239.5 mg. of residue (U.V. (EtOH): 235 m The residue is dissolved in 3 ml. of anhydrous tetrahydrofuran and the solution is added dropwise to a solution of 0.45 ml. of triethyl aluminium and 0.52 ml. of hydrocyanic acid in 7 ml. of anhydrous tetrahydrofuran under ice-cooling. Then, the mixture is sealed with a stopper and allowed to stand at room temperature for 2 hours.

After decomposition of triethyl aluminium by addition of a small amount of methanol, the mixture is poured into cold 2 N-hydrochloric acid and extracted with ether chloroform (3:1) mixture. The extract is washed'with 2 N- sodium hydroxide solution and Water, dried over anhyd-rous sodium sulfate and evaporated under reduced pres sure. The residue is crystallized from acetone-ethe pentane mixture to give 110.7 mg. of crystals. The residue of mother liquor (134.2 mg.) is chromatographed on 4 g. of alumina. From eluates with benzene, benzenechloroform (9:1) mixture and benzene-chloroform (7:3) mixture is obtained further 10.1 mg. of crystals by crystallization from acetone-ether mixture. Totally, 120.8 mg. of dl-3a-acetyloxy17-oxo-D-homo-55-androst-9( 1 1 ene-lS-nitrile is obtained. Recrystallization from acetoneether mixture gives pure product melting at 249-251 C. LR. (CHCl 2240, 1726 GEL Analysis.Calcd. for C H O N(355.46): C, 74.33; H, 8.22; N, 3.94. Found; C, 74.31; H, 8.26; N, 3.92.

Example 8 CH CO Example 8-Continued CHaCO CHgCOO under reduced pressure to give 3.2 g. of residue (trien-enol ether structure is confirmed by U.V. spectrum measurement). The residue is added to 100 m1. of 70%-acetic acid (v./v.) and heated to 90 C. to clarify the solution and then 40 ml. of Water added. The mixture is heated at 90 C. for 30 minutes, poured into ice-water and extracted with chloroform. The extract is washed with water, sodium bicarbonate solution and water in turn, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 2.80 g. of residue.

7 The residue is dried Well and dissolved in 30 ml. of anhydrous'tetrahydrofiuran. This solution is added to a mixture of 3.62 g. of triethyl aluminium, 1.08 g. of hydrocyanic acid and 50 ml. of anhydrous tetrahydrofuran under icecooling. After 20 minutes, the mixture is sealed with a stopper and allowed to stand at roorn temperature over night. After decomposition of excess of triethyl aluminium by addition of 6 ml. of ethanol under ice-cooling, the mixture is poured into ice-water and extracted with ether.

The extract is washed with water,

dried over anhydrous sodium sulfate and evaporated uncrystallization with ether. Totally, 1.53 g. of dl-3u-acet' yloxy-17oxo-Dhomo-5e-androst-9 (-1 1 -ene-1 8 nitrile is obtained,

is Example 9 CN 7 W p CHsCOO--- CHaCOO I washed with 2 N-sodium carbonate solution and water until the Washing shows no acidity, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is crystallized from acetone-ether mixture to give 78.6 mg. of dl-3a-acetyloxy-17,17-ethylenedioxy-D- homo-5fl-androst-9Ql1)-ene-1 8-nitrile melting at 247- 251 C. .Reorystallization from acetone-ether mixture gives pure product melting at 251-252 C. asneedle's'. LR. (CHCI 2248, 1725, 1063 cm.

Analysis.Calcd. for C H O N(-399.51): C, 72.15; H, 8.33. Found: C, 71.92; H, 8.44.

Example 10 I 0 l N} 0113000 H onsooo To a solution of 300 mg. of lithium aluminium hydride in 20 ml. of anhydrous tetrahydrofuran is added dropwise another solution of 300 mg..of dl-3wacetyloxy-l7 ,17- ethylene-dioxy-D-homo-5B-androst-9 1 1)-ene-18-nitrile in 50 ml. of anhydrous tetrahydrofuran at 0 C. with stirring. The dropwise addition'takes 2O minutes. After the addition, the mixture is stirred for further 2 hours at room temperature. Excess of lithium aluminium hydride is decomposed by addition ofwater under icecooling and the mixture is diluted with large amount of Water under ice-cooling and extracted with chloroform; The extract is Washed with Water, dried over anhydrous sodium sulfate and evaporated. under reduced pressure to give 350.5 mg. of residue. The residue is dissolved in 45 ml. of methanol and a solution of 3.36 g. of sodium hydroxide in 7 ml. of water is added. Then, the mixture is refluxed on an oil bath under nitrogen current for about 7 hours during which 5 ml. of methanol is supplied and allowed to stand over night at room temperature. Then, a solution of 1.3 g. of sodium hydroxide in 1.5 ml. of water and 2 ml. of methanol are added and the mixture is refluxed for 8.7 hours under the same condition. IR. spectrum measurement of a sample of the reaction mixture shows a strong absorption band attributable to an aldehyde function. The reaction mixture is diluted with a large amount of water and extracted with chloroform. The extract is washed with l%-tartaric acid and twice with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 258.3 mg. of neutral residue.

To a solution of the residue in 8.5 ml. of triethylene glycol are added 440 mg. of potassium hydroxide and 1.3 ml. of 80%-hydrazine-hydrate and the mixture is gradually heated on an oil bath. The temperature is slowly raised to 130-140 C. Then, the mixture is kept at the said temperature for 1 hour, wherein excess of hydrazinehydrate and resulted water is distilled off. Then, taking 50 minutes, the temperature is slowly raised to 210 C and the mixture is heated for 3 hours at 210220 C., during which nitrogen gas is violently generated. After cooling the mixture is diluted with water and extracted with chloroform. The extract is washed twice with 10%- tartaric acid and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 199.1 mg. of neutral residue. The residue is dissolved in 1.5 ml. of acetic anhydride and 1.5 ml. of anhydrous pyridine and the mixture is allowed to stand at room temperature for 1 night. Thus obtained crude acetyl product is chromatographed on 8 g. of neutral alumina. From eluates with petroleum ether-benzene (8:2) mixture, petroleum ether-benzene (7:3) mixture and petroleurn ether-benzene (6:4) mixture is obtained 123 mg. of dl-3wacetyloxy-17,17-ethlyene-dioxy-D-homo 5,6 androst-9(l1)-ene melting at 124-125 C. by recrystallization from ether-pentane mixture. Further recrystallization from ether-pentane mixture gives pure product melting at 125-127 C. as plates. LR. (CHCl 3600, 3440, 1100, 1075 cmr Analysis.Calcd. for C H O (388.53): C, 74.19; H, 9.34. Found: C, 74.95, H, 9.48

Example 11 CHaCOO- A solution of 110 mg. of dl-3cx-acetyloxy-17,l7-ethylene-dioxy-D-homo5fi-androst-9(ll)-ene in 5 m1. of acetic acid and 2.5 ml. of water is heated on a water bath, and concentrated under reduced pressure. The concentrate is diluted with water and extracted with ether-chloroform (3:1) mixture. The extract is washed with 7%-sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 97.3 mg. of crystalline residue. Crystallization from ether-pentane mixture gives 88.9 mg. of dl-3a-acetyloxy-D-h0rno-5,8-audrost-9 (1 1 -en- 17 -one. Recrystalliza tion from ether pentane mixtures gives pure product 18 melting at 155156.5 C. as leaflets. LR. (CI-1G 1710 (a little broad).

Analysis.-Calcd. for C l-1 0 64448): C, 76.70; H, 9.36. Found: C, 76.79; H, 9.57

Example 12 To a solution of 600 mg. of lithium aluminium hydride in 30 ml. of anhydrous tetrahydrofuran is added dropw-ise another solution of 1.1 g. of dl-3wacetyloxy-l7,17-ethylene-dioxy-D-homo-5fi-androst-9 1 1 -ene-18-nitrile in 20 ml. of anhydrous tetrahydroturan at 0 C. with stirring. The dr-opwise addition takes 20 minutes. Then, the mixture is stirred for 2.5 hours at 0 C. and the excess of lithium aluminium hydride is decomposed by addition of 50 m1. of ice-water. The mixture is diluted with a large amount of water and extracted with chloroform. The extract is Washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 1.07 g. of residue. The residue is dissolved in ml. of methanol and a solution of 6 g. of sodium hydrox ide in 20 ml. of water. The mixture is refluxed for 3 hours and concentrated under reduced pressure. The concentrate is diluted with ice-water and xtracted with chloroform. The extract is Washed twice with 10%-tartaric acid, with 2 N-sodium carbonate and with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 953 mg. of residue.

The residue is suspended in 34 ml. of triethylene glycol and 1.8 g. of potassium hydroxide and .6 ml. of hydrazinehydrate are added. The mixture is heated slowly to 130:2" C. and the temperature is kept at the said range for 1 hour, wherein excess of hydrazine-hydrate and re sulting water .are distilled oflt in the same manner as in the former example. Then, the temperature is slowly raised to 2110" C. and the mixture is heated at 210-220" C. for 3 hours. The mixture is poured into ice-water and extracted with chloroform. The extract is washed twice with 10%-tartaric acid, with 2 N-sodium hydroxide solution and with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 815.2 mg. of residue. The residue is dissolved in 30 ml. of acetic :acid and 12 ml. of water and the mixture is heated at 99 C. for 30 minutes. Treatment in the same manner as in the former example gives 697.6 mg. of residue. The residue is dissolved in 5 ml. of anhydrous pyridine and 3 ml. of acetic anhydride and the mixture is allowed to stand at room temperature for 1 night. Thus obtained crude acetate is crystallized from ether-pentane mixture to give 435 mg. of crystals. 350 mg. of residue obtained from the mother liquor is chromatographed on 8 g. of neutral CHsCOO--- CHaCOO--- enemasalumina. From eluates with petroleum ether-benzene (8:2) mixture, petroleum ether-benzene (7:3) mixture, petroleum ether-benzene (5:5) mixture .and petroleum ether-benzene (3:7) mixture is obtained further 145.9 mg. of crystals by crystallization from ether-pentane mixture. Totally, 580.9 mg. of dl-3a-acetyloxy-D-homo-SB-androst- 9(11)-er1-17-one is obtained.

Example 13 p :0

OH m 7 40133 CHaCOO--- To an ether solution of Grignardlagent prepared from 3 g. of methyl iodide, 550 mg. of metallic magnesium and ml. of anhydrous ether is added dropwise another solution of 580 mg. of d1-3a-acety1oxy-D-homo-5{3 androst 9(11)-en-17-one in 15 ml. of benzene with stirring under ice-cooling, the dropwise addition taking minutes. The mixture is stirred at room temperature for 1 hour. After removal of ether, 30 ml. of benzene is added and the mixture is refluxed for 2 hours. The mixture is diluted with 10%-aqueous ammonia and then with a large amount of water under ice-cooling and extracted with warm chloro form. The extract is washed twice with Water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 570 mg. of residue. The residue is dissolved' in 20 ml. of anhydrous pyridine and 12 ml. of acetic anhydride and the mixture is heated at 8090 C. for minutes. Thus obtained crude acetate is crystallized from acetone-ether mixture to give 461.6 mg. of d1- 30a .acetyloxy 17a methyl D-homo-androst-9.(11)-en- 17B ol. Recrystallization from acetoneet-her mixture gives pure product melting at 184-186 C. LR. (CHCl 3600(broad), 17 20 cmr Analysis.Calcd. for C I-I O (360.52): C, 67.62; H, 10.07. Found: C, 76.84; H, 10.28.

Example 14 on i( ijdii.

CH3COO--- To a solution of 450 mg. of dl-3a-acetyloxy-17a-methyl- D-homo-5fi-androst-9(11)-en 17[3-o1 in 3.5 ml. of anhydrous pyridine isadded dropwise 0.44 ml. of phosphorus oxychloride under ice-cooling and the mixture is heated at 6065 C. for 40 minutes. Then, the mixture is concentrated under reduced pressure and extracted with chloroform. The extract is washed with 2 N-hydrochloric acid, 2 N-sodium carbonate solution and Water in turn, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 440.7 mg. of residue containing an isomeric mixture of d1-3a-acetyloxy-17-rnethyl- D-homo-5fi-androsta-9(1 1),16-diene and dl-3u-acetyloxyl7-methyl-D-homo-5/3-androsta-9(1 l l7-diene. The residue is dissolved in 15 ml. of anhydrous benzene (free from thiophene) and a solution of 380 mg. of osmium tetroxide in 0.46 ml. of anhydrous pyridine is added under ice-cooling. The mixture is shaken to clarify and allowed to stand at room temperature for 1 night. Precipitated substances are dissolved by addition of 30 ml. of dioxane and hydrogen sulfide is blown into the mixture for 20 minutes. Precipitated osmium sulfide is removed by filtration through infusorial earth (Celit'e). trate is concentrated under reduced pressure and extracted with chloroform. The chloroform solution is washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 477.7 mg. of residue. The residue is chromatographed on neutral alumina. Prom eluates with ether and ether-pentane mixture mg. of dl-3a-acetyloxy-17oc-methyl-D-homo-5,8-androst-9 (1l)-ene-17B,17afi-diol is obtained. benzene-chloroform (9:1) mixture and benzene-chloroform (8:2) mixture is obtained 67.8 mg. of dl-3a-acetyloxy- 176 methyl D homo-5 3-androst-9(11)-ene-17a, 17aot-diol. From eluates with benzene-chloroform (8:2) mixture, benzene-chloroform (7:3) mixture, benzenechloroform (5:5) mixture, benzene-chloroform (3:7) mixture and chloroform is obtained 56.2 mg. of (ll-3c:- acetyloxy 17a methyl D-homo-5B-androst-9(11)-ene- 165,17/3-diol. From eluates with chloroform-methanol (99:1) mixture is obtained 48.3 mg. of dl-3a-acetyloxy- From eluates with (ll 3a acety-loxy 17oz methyl-D-homo-5,3-androst-9 (11)-ene-16,175-diol: fine columns melting at 205-207 C., recrystallized from acetone-ether mixture. LR. (CHCI 3550-3440, 1718 cmr Analysis.-Calcd. for C l-1 0437652): C, 73.36, H, 9.64. Found: C, 71.95; H, 9.60.

dl 3a acetyloxy 17B methyl-D-homo-5,B-androst-9 (11)-e11616oz,17a-diOlZ columns or plates melting at 196- 197 C., recrystallized from acetone-ether mixture. LR. (CHCl 3550, 1715 cmf Analysis.Calcd. for C H O (376.52): C, 73.36; H, 9.64. Found: C, 73.10; H, 9.68.

Example 15 To a solution of 100 mg. of dl-3 a-acetyloxy-UB-methyL dioxane and 2.3 ml. of methanol is added another solution of 85 mg. of periodic acid-dihydrate in 1.8 ml. of water and the mixture is allowed to stand at room temperature for 2.5 hours. The mixture is poured into ice-water and extracted 3 times with chloroform. The extract is washed with 2 N-sodium carbonate solution and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 93.3 mg. of dl-3a-acetyloxy-16-acety1- 16,17-seco-5,8-androst-9(11)-en-17-al as oily residue.

To a solution of 62 mg. of dl-3a-acetyloxy-W S-methyl- D-homo-5-androst-9(11)-ene-17e,17aa-dio1 in 2 ml. of dioxane and 1.5 ml. of methanol is added another solution of 52 mg. of periodic acid-dihydrate in 1.2 ml. of

water and the mixture is allowed to stand on for 3 hours at room temperature. Working up in the similar manner as in the Example 15, 67 mg. of dl-3a-acetyloxy-16- acetyl-16,17-seco-5fl-androst-9 1 1 -en-17-al is obtained as oily residue. LR. (CHCI 2680, 1715 CI11.'1.

Example 17 CHaCOO--- To a solution of 50 mg. of dl-3a-acetyloxy-flat-methyl- 0 D-homo-5/3-androst-9(l1)-ene-16;3,17,B-diol in 2 ml. of

dioxane and 1.5 m1. of methanol is added another solution of 42 mg. of periodic acid-dihydrate in 0.9 ml. of Water and the mixture is allowed to stand for 2 hours at room temperature. Working up in the similar manner as in the Example 15, 50 mg. of dl-3a-acetyloxy-17-acetyl-16. 17-seco-5fl-androst-9(11)-en-16-a1 is obtained as oily residue.

Example 18 CH3 p ...OH ...()]1

0 /\/\Z H CH0 To a solution of 40 mg. of dl-3a-acetyloxy-UB-methyl- D-hom-o-5fl-androst-9Ul)-enel6a,17a-diol in 1.3 ml. of dioxane and 1 ml. of methanol is added another solution of 35 mg. of periodic acid-dihydrate in 0.8 ml. of water and the mixture is allowed to stand for 4 hours at room temperature. Working up in the similar manner as in the Example 15, 49.3 mg. of dl-3a-acetyloxy-l7-acetyl-16, 17-seco-5B-androst-9U1)-ene-16-al is obtained as oily residue. LR. (CI-1G 2700, 1715 cmr Example 19 CIIaCOO-- GHsCOO-- To a solution of 160 mg. of oily cll3a-acetyloxy-l6- acetyl-16,17-seco-5Bandrost-9(l1)-en-17-al in 4 ml. of xylene is added 4 ml. of a xylene mixture prepared by dissolving 0.864 ml. of acetic acid and 1.4 ml. of triethyl amine in 10 ml. of xylene and the mixture is sealed under 0.6 mm. Hg pressure. Then, the sealed tube is heated for 8 hours in a boiling xylene bath. After cooling, the reactionmixture is extracted with chloroform. The extract is Washed with 2 N-hydrochloric acid, 2 N-sodium carbonate solution and water in turn, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 172.6 mg. of residue. The residue is chromatographed on 8 g. of neutral alumina and from eluates with petroleum ether-benzene (8:27:3) mixture is obtained 76.8 mg. of dl-3a-acetyloxy-l6-acetyl-5fi-androsta-9( 11), 16-diene melting at 113-115 C. by crystallizing from ether-pentane mixture. Recrystallization from ether-pentane mixture gives pure product melting at 116-1 17 C. as fine needles. U.V. (EtOH): 206 m (e 4,730); 238 my. (6 9,690). LR. (CS 1728, 1660, 1238 cmr' Analysis.-Calcd. for C H O (356.49): C, 77.49; H, 9.05. Found: C, 77.76; H, 9.22.

Example 20 CHaCOO To a solution of 100 mg. of oily dl-3a-acetyloxy-l7 acetyl-16,17-seco-fl-androsta-9(1l)-en-16-al in 2.5 ml. of xylene is added 2.5 ml. of the xylene mixture prepared in the Example 19 and the mixture is sealed under 0.6 mm. Hg pressure. a boiling xylene bath. Treating the mixture in the similar manner as in the Example 19, 94.2 mg. of residue is obtained. The residue is chromatographed on 4 g. of neutral alumina and from eluates with petroleum etherbenzene (8:2-7:3) mixture is obtained 19.6 mg. of dl-3aacetyloxy-5fi-pregna-9 1 l ,l 6-dien-20-one by recrystallization from ether-pentane mixture or methanol. A further recrystallization from methanol or ether-pentane mix- 7 ture gives pure product melting at 153-155 C. as fine columns. U.V. (EtOH): 206 III/L (6 4,880), 238 m (6 6,960). LR. (CS 1725, 1660, 1240 cm.-

Analysis.--Calcd. for C H O (356.49): C, 77.49; H, 9.05. Found: C, 76.75; H, 9.15. 9

Of the compounds hereinbefore specifically set forth, the compounds having a ketalized oxo radical and/oran acylated hydroxyl radical can be deketalized and/or deacylated in a conventional manner to give the corresponding free 0x0 and/ or hydroxyl compounds.

Then, sealed tube is heated for 8 hours in I claim: 1. A compound of the formula:

ROW 2 wherein R is a lower alkanoyl group and R is a lower alkyl group.

2. 30a acetyloxy 17 ethoxy D homo 18 nor- 5 ,8-androsta -9 1 l ,l2,l7-triene.

3. A compound ofthe formula:

.ROMN

wherein R is a lower alkanoyl group.

4. 3oz acetyloxy D homo 18 nor 58 androsta- 9(11),l3(17a)-dien-17-one.

5. A compound of the formula:

Row

wherein R is a lower alkanoyl group.

6. 3oz-acetyloxy-'17-oxo-D-homo-5fl-androst-9 1 1)-ene- 18-nitrile.

7. A compound of the formula:

wherein R is a lower alkanoyl group.

10. 3wacetyloxy-D-homo-5,B-androst-9( l 1)-en-,17-one.

25 11. A compound of the formula:

wherein R is a lower alkanoyl group and A is a lower 10 alkylene group.

1-2. 3a-acety'loxy 17,17-ethylenedioxy-D-homo-Sfi-androst-9 1 1 -ene.

13. A compound of the formula:

wherein R is a lower alkanoyl group.

14. 3a-acetyloxy 17a-methyl D homo Sfi-androst- 25 9(1l)en-17fl-o1.

15. A compound of the formula:

i CH

R0 Iwv wherein R is a lower alkanoyl group;

2% 16. 3wacety1oXy-1 7-metl1yl- D-hom o-Sfl-androsta-9 1:1 16-d-iene.

17. A compound of the formula;

RONW g wherein R is a lower alkanoyl group.

18. 3u-acetyloxy-17-acety1 16,17 seco-Sfl-androsta- WALTER A. MODANCE, Primary Examiner.

35 NICHOLAS S. RIZZO, Examiner. 

1. A COMPOUND OF THE FORMULA: 